Microcircuitry and functional architecture of the cat retina.

Sterling P, Freed M, Smith RG

Department of Neuroscience, University of Pennsylvania, Philadelphia 19104, USA.

Neurons in cat retina belong to specific types. Each type is
characterized by a specific correspondence between morphology and
physiology and forms a regular array that connects lawfully to
the arrays of certain other types. Two circuits have been traced
quantitatively through these arrays from photoreceptors to alpha-
and beta- ganglion cells. The 'cone-bipolar circuit' appears to
convey the center-surround receptive field to ganglion cells,
using cones in daylight and rods (via gap junctions to cones) in
twilight. A 'rod-bipolar circuit' appears to convey the quantal
signal and the pure center receptive field to the ganglion cells
in starlight.

Montage: a system for three-dimensional reconstruction by personal computer.

Smith RG

Department of Anatomy, School of Medicine, University of Pennsylvania, Philadelphia 19104-6058.

This paper describes a simplified system for serial section three-dimensional (3-D) reconstruction. A set of 9 software programs runs on a standard personal computer and produces camera-ready illustrations suitable for publication. The user enters trace points on a digitizing tablet from sections that have been already aligned. A 3-D view of the reconstructed object is generated which can be displayed with hidden lines removed. Analysis of volume, surface area and autoradiographic grain density are performed automatically. A relational database query language allows display and analysis of a selected subset of the data. The system runs under the UNIX operating system which allows the programs to be easily transported to new hardware or modified for other purposes.

Smith RG

Department of Anatomy, University of Pennsylvania, Philadelphia 19104-6058.

A computational language was developed to simulate neural circuits. A model of a neural circuit with up to 50,000 compartments is constructed from predefined parts of neurons, called "neural elements". A 2-dimensional (2-D) light stimulus and a photoreceptor model allow simulating a visual physiology experiment. Circuit function is computed by integrating difference equations according to standard methods. Large-scale structure in the neural circuit, such as whole neurons, their synaptic connections, and arrays of neurons, are constructed with procedural rules. The language was evaluated with a simulation of the receptive field of a single cone in cat retina, which required a model of cone-horizontal cell network on the order of 1000 neurons. The model was calibrated by adjusting biophysical parameters to match known physiological data. Eliminating specific synaptic connections from the circuit suggested the influence of individual neuron types on the receptive field of a single cone. An advantage of using neural elements in such a model is to simplify the description of a neuron's structure. An advantage of using procedural rules to define connections between neurons is to simplify the network definition.

Simulation of an anatomically defined local circuit: the cone-horizontal cell network in cat retina.

Smith RG

Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.

The outer plexiform layer of the retina contains a neural
circuit in which cone synaptic terminals are electrically coupled
and release glutamate onto wide-field and narrow-field horizontal
cells. These are also electrically coupled and feed back through
a GABAergic synapse to cones. In cat this circuit's structure is
known in some detail, and much of the chemical architecture and
neural responses are also known, yet there has been no attempt to
synthesize this knowledge. We constructed a large-scale
compartmental model (up to 50,000 compartments) to incorporate
the known anatomical and biophysical facts. The goal was to
discover how the various circuit components interact to form the
cone receptive field, and thereby what possible function is
implied. The simulation reproduced many features known from
intracellular recordings: (1) linear response of cone and
horizontal cell to intensity, (2) some aspects of temporal
responses of cone and horizontal cell, (3) broad receptive field
of the wide-field horizontal cell, and (4) center-surround cone
receptive field (derived from a "deconvolution model").
With the network calibrated in this manner, we determined which
of its features are necessary to give the cone receptive field a
Gaussian center-surround shape. A Gaussian-like center that
matches the center derived from the ganglion cell requires both
optical blur and cone coupling: blur alone is too narrow,
coupling alone gives an exponential shape without a central
dome-shaped peak. A Gaussian-like surround requires both types of
horizontal cell: the narrow-field type for the deep, proximal
region and the wide-field type for the shallow, distal region.
These results suggest that the function of the cone-horizontal
cell circuit is to reduce the influence of noise by
spatio-temporally filtering the cone signal before it passes
through the first chemical synapse on the pathway to the brain.

Microcircuitry of the dark-adapted cat retina: functional architecture of the rod-cone network.

Smith RG, Freed MA, Sterling P

The structure of the rod-cone network in the area centralis of
cat retina was studied by reconstruction from serial electron
micrographs. About 48 rods converge on each cone via gap
junctions between the rod spherules and the basal processes of
the cone pedicle. One rod diverges to 2.4 cones through these gap
junctions, and each cone connects to 8 other cones, also through
gap junctions. A static cable model of this network showed that
at mesopic intensities, when all rods converging on a cone
pedicle are continuously active, the collective rod signal would
be efficiently conveyed to the pedicle. At scotopic intensities
sufficiently low for only one of the converging rods to receive a
single photon within its integration time, the quantal rod signal
would be poorly transmitted to the cone pedicle. This is because
the tiny signal would be dissipated by the large network into
which the individual rod diverges. Under this condition, the rod
signal would also be poorly conveyed to the rod spherule. If,
however, the rods are electrically disconnected from the network,
the quantal signal would be efficiently conveyed to the rod
spherule. This analysis suggests that the rod signal is conveyed
at mesopic intensities by the cone bipolar pathway and, at
scotopic intensities, by the rod bipolar pathway, in accordance
with the results of Nelson (1977, 1982; Nelson and Kolb, 1985).

Cone receptive field in cat retina computed from microcircuitry.

Smith RG, Sterling P

Department of Anatomy, School of Medicine, University of Pennsylvania,
Philadelphia.

The receptive-field profile of the cone in cat-retina was computed. The computation
was based on (1) the known anatomical circuit connecting cones via narrow-field
bipolar cells to the on-beta ganglion cell; (2) the known physiological receptive-field
profile of the on-beta (X) cell at the corresponding eccentricity; and (3) a model in
which the beta receptive field arises by linear superposition of cone receptive fields.
The computed cone receptive field has a center/surround organization with a center
almost as broad as that of the beta cell center. The cone surround is comparably broad
to that of the beta cell but somewhat lower in peak amplitude. The problems to which
the center/surround receptive field are the solution, namely, signal compression and
noise reduction, apparently must be solved before the first synapse of the visual
pathway.

Smith RG, Vardi N

Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.

The AII amacrine cell of mammalian retina collects signals from several hundred rods
and is hypothesized to transmit quantal "single-photon" signals at scotopic (starlight)
intensities. One problem for this theory is that the quantal signal from one rod when
summed with noise from neighboring rods would be lost if some mechanism did not
exist for removing the noise. Several features of the AII might together accomplish
such a noise removal operation: The AII is interconnected into a syncytial network by
gap junctions, suggesting a noise-averaging function, and a quantal signal from one rod
appears in five AII cells due to anatomical divergence. Furthermore, the AII contains
voltage-gated Na+ and K+ channels and fires slow action potentials in vitro,
suggesting that it could selectively amplify quantal photon signals embedded in
uncorrelated noise. To test this hypothesis, we simulated a square array of AII somas
(Rm = 25,000 Ohm-cm2) interconnected by gap junctions using a compartmental
model. Simulated noisy inputs to the AII produced noise (3.5 mV) uncorrelated
between adjacent cells, and a gap junction conductance of 200 pS reduced the noise by
a factor of 2.5, consistent with theory. Voltage-gated Na+ and K+ channels (Na+: 4
nS, K+: 0.4 nS) produced slow action potentials similar to those found in vitro in the
presence of noise. For a narrow range of Na+ and coupling conductance, quantal
photon events (approximately 5-10 mV) were amplified nonlinearly by subthreshold
regenerative events in the presence of noise. A lower coupling conductance produced
spurious action potentials, and a greater conductance reduced amplification. Since the
presence of noise in the weakly coupled circuit readily initiates action potentials that
tend to spread throughout the AII network, we speculate that this tendency might be
controlled in a negative feedback loop by up-modulating coupling or other synaptic
conductances in response to spiking activity.

Microcircuitry of the on-beta ganglion cell in daylight, twilight, and starlight.

Sterling P, Cohen E, Freed MA, Smith RG

Department of Anatomy, University of Pennsylvania Medical School, Philadelphia 19104-6058.

Between noon and the end of nightfall, the intensity of light
in the environment declines by about ten billion-fold. MOst of
the drama in the human experience of this change occurs during
the hours that we call "twilight". Colors gradually shift in hue
and then desaturate, but spatial resolution is preserved for a
while longer. Thus, in a garden the red roses turn purple and
then black, but the structure of the bush remains distinct. Only
later, as the stars appear, do the details of the foliage
dissolve into shadow.

Our experience of these transitions is paralleled to some
extent by the behavior of individual ganglion cells in cat
retina. So remarkable is their capacity to adapt that they
remain responsive to visual stimuli over the full ten log unit
range of envioronmental light intensity [1]. In this essay, we
review some salient features of this adaptation process. We then
summarize recent anatomical studies of the circuits connecting
photoreceptors to the ganglion cells and speculate upon the
relation of the neural architecture to the function. Only one
type of ganglion cell is considered: the ON-center cell known to
physiologists as "X" or "brisk-sustained" and to morphologists
as "beta" [2-5]. All of the measurements considered here, both
physiological and anatomical, refer to neurons in the area
centralis.

The AII amacrine network: coupling can increase correlated activity.

Vardi N, Smith RG

Department of Neuroscience, University of Pennsylvania, Philadelphia 19104, USA. noga@retina.anatomy.upenn.edu

Retinal ganglion cells in the cat respond to single rhodopsin
isomerizations with one to three spikes. This quantal signal is
transmitted in the retina by the rod bipolar pathway: rod-->rod
bipolar-->AII-->cone bipolar-->ganglion cell. The two-dimensional
circuit underlying this pathway includes extensive convergence
from rods to an AII amacrine cell, divergence from a rod to
several AII and ganglion cells, and coupling between the AII
amacrine cells. In this study we explored the function of
coupling by reconstructing several AII amacrine cells and the gap
junctions between them from electron micrographs; and simulating
the AII network with and without coupling. The simulation showed
that coupling in the AII network can: (1) improve the
signal/noise ratio in the AII network; (2) improve the
signal/noise ratio for a single rhodopsin isomerization striking
in the periphery of the ganglion cell receptive field center, and
therefore in most ganglion cells responding to a single
isomerization; (3) expand the AII and ganglion cells' receptive
field center; and (4) expand the "correlation field". All of
these effects have one major outcome: an increase in correlation
between ganglion cell activity. Well correlated activity between
the ganglion cells could improve the brain's ability to
discriminate few absorbed external photons from the high
background of spontaneous thermal isomerizations. Based on the
possible benefits of coupling in the AII network, we suggest that
coupling occurs at low scotopic luminances.

A closer look at this apparently simple design (three
interconnected layers and five broad classes of neuron) reveals
additional complexity (Figs. 6.2, 6.3). Each neuron class is
represented by several or many specific types. Each cell
type is distinguished from others in its class by its
characteristic morphology, connections, neurochemistry, and
function (Rodieck and Brening, 1983; Sterling, 1983). This
diversity, amounting to some 80 cellular types (Kolb et al.,
1981; Sterling, 1983; Vaney, 1990), was puzzling at first, but a
broad explanation has gradually emerged: it is impossible to
encode all the information in an optical image using a single
neural image. Therefore, the retina uses different cell types to
create parallel circuits for different light levels - daylight,
twilight, and starlight - but these share certain circuit
compaonents and use the same final pathways to the brain (Smith
et al., 1986).

This chapter describes key cell types and their
interconnection in parallel circuits. It also discusses how the
functional architecture of a circuit depends on the functional
architecture of its synapses. Finally, it suggests how the flow
of visual information shifts between circuits that are
specialized for different light levels and how the circuits are
switched. The chapter focuses on mammalian retina because that
is where the combined knowledge of circuitry and cell physiology
is best known. Early efforts centered on cat, so specific
measurements, counts, etc., cited here refer to cat central
retina. But recent efforts have broadened to include rabbit, rat,
monkey, and human. These demonstrate strongly conserved patterns
in the circuitry, as well as special adaptations, and some of
both will be mentioned.

Noise removal at the rod synapse of mammalian retina.

van Rossum MC. and Smith RG.

Mammalian rods respond to single photons with a hyperpolarization
of about 1 mV which is accompanied by continuous noise. Since the
mammalian rod bipolar cell collects signals from 20-100 rods, the
noise from the converging rods would overwhelm the single-photon
signal from one rod at scotopic intensities (starlight) if the
bipolar cell summed signals linearly (Baylor et al., 1984).
However, it is known that at scotopic intensities the retina
preserves single-photon responses (Barlow et al., 1971;
Mastronarde, 1983). To explore noise summation in the rod
bipolar pathway, we simulated an array of rods synaptically
connected to a rod bipolar cell using a compartmental model. The
performance of the circuit was evaluated with a discriminator
measuring errors in photon detection as false positives and false
negatives, which were compared to physiologically and
psychophysically measured error rates. When only one rod was
connected to the rod bipolar, a Poisson rate of 80 vesicles/s was
necessary for reliable transmission of the single-photon signal.
When 25 rods converged through a linear synapse the noise caused
an unacceptably high false positive rate, even when either dark
continuous noise or synaptic noise where completely removed. We
propose that a threshold nonlinearity is provided by the mGluR6
receptor in the rod bipolar dendrite (Shiells & Falk, 1994) to
yield a synapse with a noise removing mechanism. With the
threshold nonlinearity the synapse removed most of the noise.
These results suggest that a threshold provided by the mGluR6
receptor in the rod bipolar cell is necessary for proper
functioning of the retina at scotopic intensities and that the
metabotropic domains in the rod bipolar are distinct. Such a
nonlinear threshold could also reduce synaptic noise for cortical
circuits in which sparse signals converge.
Visual Neurosci. 1998 Jul-Aug; 15(4):743-53,

Demb JB. Haarsma L. Freed MA. Sterling P.

Department of Neuroscience, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6058, USA.

A retinal ganglion cell commonly expresses two spatially
overlapping receptive field mechanisms. One is the familiar
"center/surround," which sums excitation and inhibition across a
region somewhat broader than the ganglion cell's dendritic field.
This mechanism responds to a drifting grating by modulating
firing at the drift frequency (linear response). Less familiar is
the "nonlinear" mechanism, which sums the rectified output of
many small subunits that extend for millimeters beyond the
dendritic field. This mechanism responds to a contrast-reversing
grating by modulating firing at twice the reversal frequency
(nonlinear response). We investigated this nonlinear mechanism by
presenting visual stimuli to the intact guinea pig retina in
vitro while recording intracellularly from large brisk and
sluggish ganglion cells. A contrast-reversing grating modulated
the membrane potential (in addition to the firing rate) at twice
the reversal frequency. This response was initially
hyperpolarizing for some cells (either ON or OFF center) and
initially depolarizing for others. Experiments in which responses
to bars were summed in-phase or out-of-phase suggested that the
single class of bipolar cells (either ON or OFF) that drives the
center/surround response also drives the nonlinear response.
Consistent with this, nonlinear responses persisted in OFF
ganglion cells when ON bipolar cell responses were blocked by
L-AP-4. Nonlinear responses evoked from millimeters beyond the
ganglion cell were eliminated by tetrodotoxin. Thus, to relay the
response from distant regions of the receptive field requires a
spiking interneuron. Nonlinear responses from different regions
of the receptive field added linearly.

Cost of cone coupling to trichromacy in primate fovea.

Hsu A, Smith RG, Buchsbaum G, Sterling P

Cone synaptic terminals couple electrically to their neighbors.
This reduces the amplitude of temporally uncorrelated voltage
differences between neighbors. For an achromatic stimulus coarser
than the cone mosaic, the uncorrelated voltage difference between
neighbors represents mostly noise; so noise is reduced more than
the signal. Here coupling improves signal-to-noise ratio and
enhances contrast sensitivity. But for a chromatic stimulus the
uncorrelated voltage difference between neighbors of different
spectral type represents mostly signal; so signal would be
reduced more than the noise. This cost of cone coupling to
encoding chromatic signals was evaluated using a compartmental
model of the foveal cone array. When cones sensitive to middle
(M) and long (L) wavelengths alternated regularly, and the
conductance between a cone and all of its immediate neighbors was
1000 pS (similar to 2 connexons/cone pair), coupling reduced the
difference between the L and M action spectra by nearly fivefold,
from about 38% to 8%. However, L and M cones distribute randomly
in the mosaic, forming small patches of like type, and within a
patch the responses to a chromatic stimulus are correlated. In
such a mosaic, coupling still reduced the difference between the
L and M action spectra, but only by 2.4-fold, to about 18%. This
result is independent of the L/M ratio. Thus "patchiness" of the
L/M mosaic allows cone coupling to improve achromatic contrast
sensitivity while minimizing the cost to chromatic sensitivity.

Effects of Noise on the Spike Timing Precision of Retinal
Ganglion Cells.

Information in a spike train is limited by variability in the
spike timing. This variability is caused by noise from several
sources including synapses and membrane channels, but how
deleterious each noise source is and how they affect spike train
coding is unknown. Combining physiology and a multi-compartment
model we studied the effect of synaptic input noise and
voltage-gated channel noise on spike train reliability for a
mammalian ganglion cell. For tonic stimuli the standard
deviation of the interspike intervals increased supra-linearly
with increasing interspike interval. Voltage gated channel noise
and synaptic noise caused fluctuations in the interspike interval
of comparable amplitude. Spikes initiated on the dendrites
caused additional spike timing fluctuations. Ca and KCa channels
present in the model reduced spike train variability. For
transient stimuli, synaptic noise was dominant. Spontaneous
background activity strongly increased fluctuations in spike
timing, but decreased the latency before the first spike. These
results constrain the neural coding strategy.
In: Computation in Neurons and Neural Systems" (1994) Ed. by Frank
H. Eekman. Kluwer Academic Publishers, Boston.

Electrical coupling between mammalian cones

DeVries S; Qi X; Smith R; Makous W; Sterling P

Current Biology 2002 12:1900-1907.

Background

Cone photoreceptors are noisy because of random fluctuations of
photon absorption, signaling molecules, and ion channels.
However, each cones noise is independent of the others, whereas
their signals are partially shared. Therefore, electrically
coupling the synaptic terminals prior to forward transmission and
subsequent nonlinear processing can appreciably reduce noise
relative to the signal. This signal-processing strategy has been
demonstrated in lower vertebrates with rather coarse vision, but
its occurrence in mammals with fine acuity has been doubted (even
though gap junctions are present) because coupling would blur the
neural image.

Results

In ground squirrel retina, whose triangular cone lattice
resembles the human fovea, paired electrical recordings from
adjacent cones demonstrated electrical coupling with an average
conductance of approximately 320 pS. Blur caused by this degree
of coupling had a space constant of approximately 0.5 cone
diameters. Psychophysical measurements employing laser
interferometry to bypass the eyes optics suggest that human
foveal cones experience a similar degree of neural blur and that
it is invariant with light intensity. This neural blur is
narrower than the eye's optical blur, and we calculate that it
should improve the signal-to-noise ratio at the cone terminal by
about 77%.

Conclusions

We conclude that the gap junctions observed between mammalian
cones, including those in the human fovea, represent genuine
electrical coupling. Because the space constant of the resulting
neural blur is less than that of the optical blur, the
signal-to-noise ratio can be markedly improved before the
nonlinear stages with little compromise to visual acuity.

Contrast Threshold of a Brisk-Transient ganglion cell

Dhingra NK, Kao YH, Sterling P, Smith RG

J. Neurophysiol. 2003 89: 2360-2369.

Abstract

We have measured the contrast threshold for a mammalian
brisk-transient ganglion cell. The intact retina (guinea pig) was
maintained in vitro, and extracellular spikes were recorded to a
spot with sharp onset, flashed for 100 ms over the receptive
field center. An "ideal observer" was given the spike responses
from 100 trials at each contrast and then asked to predict the
stimulus contrast on 100 additional trials in a single-interval,
two-alternative forced-choice procedure. The prediction was based
on spike count, latency or temporal pattern. Brisk-transient
cells near 37(C detected contrasts as low as 0.8% (mean ( SEM =
2.8 ( 0.2%) and discriminated contrast increments with about 40%
greater sensitivity. Performance was temperature sensitive,
declining with a Q10 ~2, similar to that of retinal metabolism.
These measurements of performance provide an important benchmark
for comparison to retinal cell types upstream of the ganglion
cell and downstream - to behavior. For example, human
psychophysical threshold for a stimulus that just covers the
dendritic field of one human brisk-transient cell is the same as
found here. This suggests that neural processing across many
levels of noisy central synapses might be highly efficient.

Timing of quantal release from the retinal bipolar terminal is
regulated by a feedback circuit

Michael A. Freed, Robert G. Smith, and Peter Sterling

Neuron 2003 38: 89-101.

Summary

In isolation, a presynaptic terminal generally releases quanta
according to Poisson statistics, but in a circuit its release
statistics might be shaped by local feedback. We monitored
quantal release of glutamate from retinal bipolar cell terminals
(which receive GABA-ergic feedback from amacrine cells) by
recording spontaneous EPSCs in their postsynaptic amacrine and
ganglion cells. EPSCs were temporally correlated in about one
third of these cells, arriving in brief bursts (~20 ms) more
often than expected from a Poisson process. Correlations were
suppressed by antagonizing the GABAC receptor (expressed on
bipolar terminals), and correlations were induced by raising
extracellular calcium or osmolarity (which increase release
probability). Simulations of the feedback circuit produced
``bursty'' release when the bipolar cell escaped intermittently
from inhibition. Correlations of similar strength and duration
were also present in light-evoked EPSCs and ganglion cell spikes.
These correlations were also suppressed by a GABAC antagonist,
indicating that bursts of glutamate from bipolar terminals induce
spike bursts in ganglion cells.

Dhingra NK and Smith RG

J. Neurosci. 2004 24: 2914-2922.

Summary

The quality of the signal a retinal ganglion cell transmits to
the brain is important for preception because it sets the minimum
detectable stimulus. The ganglion cell converts graded potentials
into a spike train with a selective filter but in the process
adds noise. To explorehow efficiently information is transferred
to spikes, we measured contrast detection threshold and increment
threshold from graded potential and spike responses of
brisk-transient ganglion cells. Intracellular responses to a spot
flashed over the receptive field center of the cell were recorded
in an intact mammalian retina maintained in vitro at 37°C.
Thresholds were measured in a single-interval forced-choice
procedure with an ideal observer. The graded potential gave a
detection threshold of 1.5% contrast, whereas spikes gave 3.8%.
The graded potential also gave increment thresholds approximately
twofold lower and carried 60% more gray levels. Increment
threshold dipped below the detection threshold at a low
contrast ( < 5%) but increased rapidly at higher contrasts. The
magnitude of the dipper for both graded potential and spikes
could be predicted from a threshold nonlinearity in the
responses. Depolarization of the cell by current injection
reduced the detection threshold for spikes but also reduced the
range of contrasts they can transmit. This suggests that contrast
sensitivity and dynamic range are related in an essential
trade-off.

How efficiently a ganglion cell codes the visual signal

Smith RG, Dhingra NK, Kao YH, Sterling P

The retina's visual message is transmitted to the brain by
ganglion cells that integrate noisy synaptic inputs to create a
spike train. We asked how efficiently the retinal ganglion cell
spike generator creates the spike train message. Intracellular
and extracellular recordings were made from in vitro guinea pig
retina, in response to a spot of light flashed over the receptive
field center. Responses were analyzed with an "ideal observer," a
program that discriminated between two contrasts based on an
optimal decision rule. Spike trains from ganglion cells had
thresholds as low as 1% contrast, but thresholds for the
corresponding graded potentials were lower by a factor of 2.
Using a computational model of the ganglion cell, we asked what
factors in the spike generator mechanism are responsible for the
spike train's loss in performance. The model included
dendritic/axonal morphology, noisy synaptic inputs and membrane
channels. Adaptation of spike rate was provided by K(Ca) channels
which were activated by Ca2+ flux during spikes. When K(Ca)
channels were included, they controlled the duration of the
inter-spike interval and thus set the level of noise in the spike
train. These results imply that the spike generator adds noise to
the spike train signal.

Direction selectivity in a model of the starburst amacrine cell

Tukker JJ Taylor WR, and Smith RG

Visual Neuroscience (2004) 21: 611-625.

Summary

The starburst amacrine cell (SBAC), found in all mammalian
retinas, is thought to provide the directional inhibitory input
recorded in On-Off direction selective ganglion cells (DSGCs).
While voltage recordings from the somas of SBACs have not shown
robust direction selectivity (DS), the dendritic tips of these
cells display direction-selective calcium signals, even when
gamma aminobutyric acid (GABAa,c) channels are blocked, implying
that inhibition is not necessary to generate DS. This suggested
that the distinctive morphology of the starburst could generate a
DS signal at the dendritic tips, where most of its synaptic
output is located. To explore this possibility, we constructed a
compartmental model incorporating realistic morphological
structure, passive membrane properties, and excitatory inputs. We
found robust direction selectivity at the dendritic tips but not
at the soma. Thin bars produced robust DS, but two-spot apparent
motion and annulus radial motion gave little DS. For these
stimuli, DS was caused by the interaction of a local synaptic
input signal with a temporally delayed "global" signal, that is,
an excitatory postsynaptic potential (EPSP) that spread from the
activated inputs into the soma and throughout the dendritic tree.
In the preferred direction the signals in the dendritic tips
coincided, allowing summation, whereas in the null direction the
local signal preceded the global, preventing summation. Sine-wave
gratings gave the greatest amount of DS, especially at high
velocities and low spatial frequencies. The sine-wave DS
responses could be accounted for by a simple model which summed
phase-shifted signals from different parts of the cell. By
testing different artificial morphologies, we discovered DS was
relatively independent of the detailed morphology, but depended
on having a sufficient number of inputs at the distal tips and a
limited electrotonic isolation. Adding voltage-gated calcium
channels to the model showed that their threshold effect can
amplify DS in the intracellular calcium signal.

Transmission of scotopic signals from the rod to rod-bipolar cell
in the mammalian retina.

Taylor WR, and Smith RG

Vision Research (2004) 44: 3269-3276.

Summary

Mammals can see at low scotopic light levels where only 1 rod in
several thousand transduces a photon. The single photon signal is
transmitted to the brain by the ganglion cell, which collects
signals from more than 1000 rods to provide enough amplification.
If the system were linear, such convergence would increase the
neural noise enough to overwhelm the tiny rod signal. Recent
studies provide evidence for a threshold nonlinearity in the rod
to rod bipolar synapse, which removes much of the background
neural noise. We argue that the height of the threshold should be
0.85 times the amplitude of the single photon signal, consistent
with the saturation observed for the single photon signal. At
this level, the rate of false positive events due to neural noise
would be masked by the higher rate of dark thermal events. The
evidence presented suggests that this synapse is optimized to
transmit the single photon signal at low scotopic light levels.

Transmission of single photon signals through a binary synapse in
the mammalian retina

Berntson A, Smith RG, and Taylor WR

Visual Neurosci. (2004) 21:693-702

Summary

At very low light levels the sensitivity of the visual system is
determined by the efficiency with which single photons are
captured, and the resulting signal transmitted from the rod
photoreceptors through the retinal circuitry to the ganglion
cells and on to the brain. Although the tiny electrical signals
due to single photons have been observed in rod photoreceptors,
little is known about how these signals are preserved during
subsequent transmission to the optic nerve. We find that the
synaptic currents elicited by single photons in mouse rod bipolar
cells have a peak amplitude of 5-6 pA, and that about 20 rod
photoreceptors converge upon each rod bipolar cell. The data
indicates that the first synapse, between rod photoreceptors and
rod bipolar cells, signals a binary event: the detection, or not,
of a photon or photons in the connected rod photoreceptors. We
present a simple model that demonstrates how a threshold
nonlinearity during synaptic transfer allows transmission of the
single photon signal, while rejecting the convergent neural noise
from the 20 other rod photoreceptors feeding into this first
synapse.

Postsynaptic calcium feedback between rods and rod bipolar
cells in the mouse retina

Berntson A, Smith RG, and Taylor WR

Visual Neurosci. (2004) 21:913-924

Summary

Light-evoked currents were recorded from rod bipolar cells in a
dark-adapted mouse retinal slice preparation. Low-intensity light
steps evoked a sustained inward current. Saturating light steps
evoked an inward current with an initial peak that inactivated,
with a time constant of about 60-70 ms, to a steady plateau level
that was maintained for the duration of the step. The
inactivation was strongest at hyperpolarized potentials, and
absent at positive potentials. Inactivation was mediated by an
increase in the intracellular calcium concentration, as it was
abolished in cells dialyzed with 10 mM BAPTA, but was present in
cells dialyzed with 1 mM EGTA. Moreover, responses to brief
flashes of light were broader in the presence of intracellular
BAPTA indicating that the calcium feedback actively shapes the
time course of the light responses. Recovery from inactivation
observed for paired-pulse stimuli occurred with a time constant
of about 375 ms. Calcium feedback could act to increase the
dynamic range of the bipolar cells, and to reduce variability in
the amplitude and duration of the single-photon signal. This may
be important for nonlinear processing at downstream sites of
convergence from rod bipolar cells to AII amacrine cells. A model
in which intracellular calcium rapidly binds to the light-gated
channel and reduces the conductance can account for the results.

Sluggish and brisk ganglion cells detect contrast with similar
sensitivity

Xu Y, Dhingra NK, Smith RG, Sterling P

J. Neurophysiol. (2005) 93:2388-2395

Summary

Roughly half of all ganglion cells in mammalian retina belong to
the broad class, termed "sluggish". Many of these cells have
small receptive fields and project via lateral geniculate nuclei
to visual cortex. However, their possible contributions to
perception have been largely ignored because sluggish cells seem
to respond weakly compared to the more easily studied "brisk"
cells. By selecting small somas under infrared DIC optics and
recording with a loose seal, we could routinely isolate sluggish
cells. When a spot was matched spatially and temporally to the
receptive field center, most sluggish cells could detect the same
low contrasts as brisk cells. Detection thresholds for the two
groups determined by an "ideal observer" were similar: threshold
contrast for sluggish cells was 4.7 ± 0.5% (mean ± SE), and for
brisk cells was 3.4 ± 0.3% (Mann-Whitney test: p>0.05).
Signal-to-noise ratios for the two classes were also similar at
low contrast. However, sluggish cells saturated at somewhat lower
contrasts (contrast for half-maximum response was 14 ± 1% vs. 19
± 2% for brisk cells) and were less sensitive to higher temporal
frequencies (when the stimulus frequency was increased from 2 Hz
to 4 Hz, the response rate fell by 1.6-fold). Thus the sluggish
cells covered a narrower dynamic range and a narrower temporal
bandwidth, consistent with their reported lower information
rates. Because information per spike is greater at lower firing
rates, sluggish cells may represent "cheaper" channels that
convey less urgent visual information at a lower energy cost.

Dhingra NK, Freed, MA, Smith RG

J. Neurosci. (2005) 25:8097-8103

Summary

Voltage-gated channels in a retinal ganglion cell are necessary
for spike generation. However, they also add noise to the graded
potential and spike train of the ganglion cell, which may degrade
its contrast sensitivity, and they may also amplify the graded
potential signal. We studied the effect of blocking Na+ channels
in a ganglion cell on its signal and noise amplitudes and its
contrast sensitivity. A spot was flashed at 1- 4 Hz over the
receptive field center of a brisk transient ganglion cell in an
intact mammalian retina maintained in vitro. We measured signal
and noise amplitudes from its intracellularly recorded graded
potential light response and measured its contrast detection
thresholds with an "ideal observer." When Na+ channels in the
ganglion cell were blocked with intracellular lidocaine N-ethyl
bromide (QX-314), the signal-to-noise ratio (SNR) decreased (p <
0.05) at all tested contrasts (2-100%). Likewise, bath
application of tetrodotoxin (TTX) reduced the SNR and contrast
sensitivity but only at lower contrasts (50%), whereas at higher
contrasts, it increased the SNR and sensitivity. The opposite
effect of TTX at high contrasts suggested involvement of an
inhibitory surround mechanism in the inner retina. To test this
hypothesis, we blocked glycinergic and GABAergic inputs with
strychnine and picrotoxin and found that TTX in this case had the
same effect as QX-314: a reduction in the SNR at all contrasts.
Noise analysis suggested that blocking Na+ channels with QX-314
or TTX attenuates the amplitude of quantal synaptic voltages.
These results demonstrate that Na+ channels in a ganglion cell
amplify the synaptic voltage, enhancing the SNR and contrast
sensitivity.

Design of a Neuronal Array

Borghuis BG, Ratliff CP, Smith RG, Sterling P, Balasubramanian V.

J. Neurosci. (2008) 28:3178-3189.

Summary

Retinal ganglion cells of a given type overlap their dendritic
fields such that every point in space is covered by three to four
cells. We investigated what function is served by such extensive
overlap. Recording from pairs of ON or OFF brisk-transient
ganglion cells at photopic intensities, we confirmed that this
overlap causes the Gaussian receptive field centers to be spaced
at2 SDs (). This, together with response nonlinearities and
variability, was just sufficient to provide an ideal observer
with uniform contrast sensitivity across the retina for both
threshold and suprathreshold stimuli. We hypothesized that
overlap might maximize the information represented from natural
images, thereby optimizing retinal performance for many tasks.
Indeed, tested with natural images (which contain statistical
correlations), a model ganglion cell array maximized information
represented in its population responses with 2spacing, i.e., the
overlap observed in the retina. Yet, tested with white noise
(which lacks statistical correlations), an array maximized its
information by minimizing overlap. In both cases, optimal overlap
balanced greater signal-to-noise ratio (from larger receptive
fields) against greater redundancy (because of larger receptive
field overlap). Thus, dendritic overlap improves vision by taking
optimal advantage of the statistical correlations of natural
scenes.

Xu, Y, Sulaiman, P, Fedderson, R., Liu, J., Smith, R.G. and Vardi, N.

J. Neurosci. (2008) 28:8873-8884.

Summary

PCP2, a member of the GoLoco domain-containing family, is present
exclusively in cerebellar Purkinje cells and retinal ON-bipolar
cells. Its function in these tissues is unknown. Biochemical and
expression system studies suggest that PCP2 is a guanine
nucleotide dissociation inhibitor, though a guanine nucleotide
exchange factor has also been suggested. Here we studied the
function of PCP2 in ON bipolar cells because their light response depends
on Gao1, which is known to interact with PCP2. We identified a
new splice variant of PCP2 (Ret-PCP2) and localized it to rod
bipolar and ON cone bipolar cells. Electroretinogram recordings from PCP2-null
mice showed a normal a-wave but a slower falling phase of the b-wave (generated by
activity of ON bipolar cells) relative to the wild type.
Whole-cell recordings from rod bipolar cells showed, both under
Ames solution and after blocking GABAA/C and glycine receptors,
that PCP2-null rod bipolar cells were more depolarized than wild
type cells with greater inward current when clamped to -60 mV.
Also under both conditions, the rise time of the response to
intense light was slower by 28% (Ames) and 44% (inhibitory
blockers) in the null cells. Under Ames we also observed >30%
longer decay time in the PCP2 null rod bipolar cells. We conclude
that PCP2 facilitates cation channels' closure in the dark,
shortens the rise time of the light response directly, and
accelerates the decay time indirectly via the inhibitory network.
These data can be most easily explained if Ret-PCP2 serves as a
guanine nucleotide exchange factor.

Yin L, Smith, R.G., Sterling, P. and Brainard D.H

J. Neurosci. (2008) 29:2706-2724.

Summary

Most mammals are dichromats, having short-wavelength sensitive
(S) and middle-wavelength sensitive (M) cones. Smaller
terrestrial species commonly express a dual gradient in opsins,
with M opsin concentrated superiorly and declining inferiorly,
and vice-versa for S opsin. Some ganglion cells in these retinas
combine S and M-cone inputs antagonistically, but no direct
evidence links this physiological opponency with morphology; nor
is it known whether opponency varies with the opsin gradients.
By recording from more than 3000 ganglion cells in guinea pig, we
identified small numbers of color-opponent cells. Chromatic
properties were characterized by responses to monochromatic spots
and/or spots produced by mixtures of two primary lights.
Superior retina contained cells with strong S+/M- and M+/S-
opponency, whereas inferior retina contained cells with weak
opponency. In superior retina, the opponent cells had
well-balanced M and S weights, while in inferior retina the
weights were unbalanced, with the M weights being much weaker.
The M and S components of opponent cell receptive fields had
approximately the same diameter. Opponent cells injected with
Lucifer yellow restricted their dendrites to the ON stratum of
the inner plexiform layer and provided sufficient membrane area
(~2.1e+4 µm2) to collect ~3.9e+3 bipolar synapses. Two
bistratified cells studied were non-opponent. The apparent
decline in S/M opponency from superior to inferior retina is
consistent with the dual gradient and a model where photoreceptor
signals in both superior and inferior retina are processed by the
same post-receptoral circuitry.

Borghuis, B.G., Sterling, P. and Smith, R.G.

J. Neurosci. (2009) 29:3045-3058.

Summary

A low contrast spot that activates just one ganglion cell in the
retina is detected in the cell's spike train with about the same
sensitivity as it is detected behaviorally. This is consistent
with Barlow's proposal that the ganglion cell and later stages of
spiking neurons transfer information essentially without loss.
Yet, when losses of sensitivity by all preneural factors are
accounted for, predicted sensitivity near threshold is
considerably greater than behavioral sensitivity, implying that
somewhere in the brain information is lost. We hypothesized that
the losses occur mainly in the retina - where graded signals are
processed by analog circuits that transfer information at high
rates and low metabolic cost. To test this, we constructed a
model that included all preneural losses for an in vitro
mammalian retina, and evaluated the model to predict sensitivity
at the cone output. Recording graded responses postsynaptic to
the cones (from the type A horizontal cell) and comparing to
predicted preneural sensitivity, we found substantial loss of
sensitivity (4.2-fold) across the first visual synapse. Recording
spike responses from brisk-transient ganglion cells stimulated
with the same spot, we found a similar loss (3.5-fold) across the
second synapse. The total retinal loss approximated the known
overall loss, supporting the hypothesis that from stimulus to
perception, most loss near threshold is retinal.

Photoreceptors are the vertebrate retina's primary site for
transduction of light into a neural signal. The cone
photoreceptor plays a crucial role in daylight vision because it
transmits fast changes in light contrast. To improve its
sensitivity over 5 log units of background illumination, the cone
contains several mechanisms for adaptation: the transduction
cascade, biophysical properties, and in the ribbon synapse. The
ribbon is part of a complex local circuit called the triad that
combines adaptation with spatial filtering to maximize the amount
of information the cone transmits to second-order neurons.

The rod photoreceptor is responsible for vision at night over the
range of starlight through moonlight to twilight. In starlight,
the rod receives a photon about once in 20 minutes, requiring
spatial summation, but this would amplify the dark noise if the
visual pathway were linear. The rod synapse is specialized to
transmit single-photon signals by removing the dark continuous
noise with a threshold nonlinearity. At twilight, the rod
receives more than one photon per integration time (~200 ms in
mammals) and thus cannot transmit single-photon signals. Instead
its signals at twilight are coupled to cones through gap
junctions.

Smith, R.G. and Dhingra, N.K.

Progress in Retinal and Eye Research

Refereed review article

Summary

The function of the retina is crucial, for it must encode visual
signals so the brain can detect objects in the visual world.
However, the biological mechanisms of the retina add noise to the
visual signal and therefore reduce its quality and capacity to
inform about the world. Because an organism's survival depends on
its ability to unambiguously detect visual stimuli in the
presence of noise, its retinal circuits must have evolved to
maximize signal quality, suggesting that each retinal circuit has
a specific functional role. Here we explain how an ideal observer
can measure signal quality to determine the functional roles of
retinal circuits. In a visual discrimination task the ideal
observer can measure from a neural response the increment
threshold, the number of distinguishable response levels, and the
neural code, which are fundamental measures of signal quality
relevant to behavior. It can compare the signal quality in
stimulus and response to determine the optimal stimulus, and can
measure the specific loss of signal quality by a neuron's
receptive field for non-optimal stimuli. Taking into account
noise correlations, the ideal observer can track the signal to
noise ratio available from one stage to the next, allowing one to
determine each stage's role in preserving signal quality. A
comparison between the ideal performance of the photon flux
absorbed from the stimulus and actual performance of a retinal
ganglion cell shows that in daylight a ganglion cell and its
presynaptic circuit loses a factor of ~10-fold in contrast
sensitivity, suggesting specific signal-processing roles for
synaptic connections and other neural circuit elements. The ideal
observer is a powerful tool for characterizing signal processing
in single neurons and arrays along a neural pathway.

Lipin MK, Smith RG, Taylor WR (2010)

Biological Cybernetics, Biol Cybern. 103:57-77

Summary

The outer retina removes the first-order correlation, the background light
level, and thus more efficiently transmits contrast. This removal is
accomplished by negative feedback from horizontal cell to photoreceptors.
However, the optimal feedback gain to maximize the contrast sensitivity and
spatial resolution is not known. The objective of this study was to determine,
from the known structure of the outer retina, the synaptic gains that optimize
the response to spatial and temporal contrast within natural images. We modeled
the outer retina as a continuous 2D extension of the discrete 1D model of Yagi
et al. (Proc Int Joint Conf Neural Netw 1: 787-789, 1989). We determined the
spatio-temporal impulse response of the model using small-signal analysis,
assuming that the stimulus did not perturb the resting state of the feedback
system. In order to maximize the efficiency of the feedback system, we derived
the relationships between time constants, space constants, and synaptic gains
that give the fastest temporal adaptation and the highest spatial resolution of
the photoreceptor input to bipolar cells. We found that feedback which directly
modulated photoreceptor calcium channel activation, as opposed to changing
photoreceptor voltage, provides faster adaptation to light onset and higher
spatial resolution. The optimal solution suggests that the feedback gain from
horizontal cells to photoreceptors should be approximately 0.5. The model can
be extended to retinas that have two or more horizontal cell networks with
different space constants. The theoretical predictions closely match
experimental observations of outer retinal function.

Schachter MJ, Oesch N, Smith RG, Taylor WR

PLoS Comput Biol 6(8): e1000899. doi:10.1371/journal.pcbi.1000899.

Summary

The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas
responds most strongly to a stimulus moving in a specific direction. The DSGC
initiates spikes in its dendritic tree, which are thought to propagate to the
soma with high probability. Both dendritic and somatic spikes in the DSGC
display strong directional tuning, whereas somatic PSPs (postsynaptic
potentials) are only weakly directional, indicating that spike generation
includes marked enhancement of the directional signal. We used a realistic
computational model based on anatomical and physiological measurements to
determine the source of the enhancement. Our results indicate that the DSGC
dendritic tree is partitioned into separate electrotonic regions, each summing
its local excitatory and inhibitory synaptic inputs to initiate spikes. Within
each local region the local spike threshold nonlinearly amplifies the preferred
response over the null response on the basis of PSP amplitude. Using inhibitory
conductances previously measured in DSGCs, the simulation results showed that
inhibition is only sufficient to prevent spike initiation and cannot affect
spike propagation. Therefore, inhibition will only act locally within the
dendritic arbor. We identified the role of three mechanisms that generate
directional selectivity (DS) in the local dendritic regions. First, a mechanism
for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null
side of the cell's dendritic tree and weakens it on the preferred side. Second,
spatially offset postsynaptic inhibition generates robust DS in the isolated
dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently
necessary because it is more robust across the dendritic tree. The pre- and
postsynaptic mechanisms together can overcome the local intrinsic DS. These
local dendritic mechanisms can perform independent nonlinear computations to
make a decision, and there could be analogous mechanisms within cortical
circuitry.

Taylor WR, Smith RG.

Curr Opin Neurobiol, doi:10.1016/j.conb.2011.07.001

Summary

This review focuses on recent advances in our understanding
of how neural divergence and convergence give rise to
complex encoding properties of retinal ganglion cells. We
describe the apparent mismatch between the number of cone
bipolar cell types, and the diversity of excitatory input to retinal
ganglion cells, and outline two possible solutions. One
proposal is for diversity in the excitatory pathways to be
generated within axon terminals of cone bipolar cells, and the
second invokes narrow-field glycinergic amacrine cells that can
apparently act like bipolar cells by providing excitatory drive to
ganglion cells. Finally we highlight two advances in technique
that promise to provide future insights; automation of electron
microscope data collection and analysis, and the use of the
ideal observer to quantitatively compare neural performance at
all levels.

Trenholm S, Johnson K, Li X,Smith RG, Awatramani GB (2011)

Neuron, doi 10.1016/j.neuron.2011.06.020

Summary

In the retina, presynaptic inhibitory mechanisms that
shape directionally selective (DS) responses in output
ganglion cells are well established. However, the
nature of inhibition-independent forms of directional
selectivity remains poorly defined. Here, we describe
a genetically specified set of ON-OFF DS ganglion
cells (DSGCs) that code anterior motion. This entire
population of DSGCs exhibits asymmetric dendritic
arborizations that orientate toward the preferred
direction. We demonstrate that morphological asym-
metries along with nonlinear dendritic conductances
generate a centrifugal (soma-to-dendrite) preference
that does not critically depend upon, but works in
parallel with the GABAergic circuitry. We also show
that in symmetrical DSGCs, such dendritic DS mech-
anisms are aligned with, or are in opposition to, the
inhibitory DS circuitry in distinct dendritic subfields
where they differentially interact to promote or
weaken directional preferences. Thus, pre- and post-
synaptic DS mechanisms interact uniquely in distinct
ganglion cell populations, enabling efficient DS
coding under diverse conditions.

Taylor WR, Smith RG. (2012)

Visual Neuroscience 29:73-81.

Summary

Starburst amacrine cells (SBACs) within the adult mammalian retina provide the
critical inhibition that underlies the receptive field properties of
direction-selective ganglion cells (DSGCs). The SBACs generate
direction-selective output of GABA that differentially inhibits the DSGCs. We
review the biophysical mechanisms that produce directional GABA release from
SBACs and test a network model that predicts the effects of reciprocal
inhibition between adjacent SBACs. The results of the model simulations suggest
that reciprocal inhibitory connections between closely spaced SBACs should be
spatially selective, while connections between more widely spaced cells could
be indiscriminate. SBACs were initially identified as cholinergic neurons and
were subsequently shown to contain release both acetylcholine and GABA. While
the role of the GABAergic transmission is well established, the role of the
cholinergic transmission remains unclear.

Mammalian cones respond to light by closing a cGMP-gated channel via a cascade
that includes a heterotrimeric G-protein, cone transducin, comprising GAt2, GB3
and GGt2 subunits. The function of GBG in this cascade has not been examined.
Here, we investigate the role of GB3 by assessing cone structure and function
in GB3-null mouse (Gnb3 -/-). We found that GB3 is required for the normal
expression of its partners, because in the Gnb3 -/- cone outer segments, the
levels of GAt2 and GGt2 are reduced by fourfold to sixfold, whereas other
components of the cascade remain unaltered. Surprisingly, Gnb3 cones produce
stable responses with normal kinetics and saturating response amplitudes
similar to that of the wild-type, suggesting that cone phototransduction can
function efficiently without a GB subunit. However, light sensitivity was
reduced by approximately fourfold in the knock-out cones. Because the reduction
in sensitivity was similar in magnitude to the reduction in Gat2 level in the
cone outer segment, we conclude that activation of GAt2 in Gnb3-/- cones
proceeds at a rate approximately proportional to its outer segment
concentration, and that activation of phosphodiesterase and downstream cascade
components is normal. These results suggest that the main role of GB3 in cones
is to establish optimal levels of transducin heteromer in the outer segment,
thereby indirectly contributing to robust response properties.

Abbas SY, Hamade KC, Yang EJ, Nawy S, Smith RG, Pettit DL

PLoS Comput Biol (2013) e1002969 doi:10.1371/journal.pcbi.1002969

Summary

Retinal ganglion cells receive inputs from multiple bipolar cells which must be
integrated before a decision to fire is made. Theoretical studies have provided
clues about how this integration is accomplished but have not directly
determined the rules regulating summation of closely timed inputs along single
or multiple dendrites. Here we have examined dendritic summation of multiple
inputs along On ganglion cell dendrites in whole mount rat retina. We activated
inputs at targeted locations by uncaging glutamate sequentially to generate
apparent motion along On ganglion cell dendrites in whole mount retina.
Summation was directional and dependent13 on input sequence. Input moving away
from the soma (centrifugal) resulted in supralinear summation, while activation
sequences moving toward the soma (centripetal) were linear. Enhanced summation
for centrifugal activation was robust as it was also observed in cultured
retinal ganglion cells. This directional summation was dependent on
hyperpolarization activated cyclic nucleotide-gated (HCN) channels as blockade
with ZD7288 eliminated directionality. A computational model confirms that
activation of HCN channels can override a preference for centripetal summation
expected from cell anatomy. This type of direction selectivity could play a
role in coding movement similar to the axial selectivity seen in locust
ganglion cells which detect looming stimuli. More generally, these results
suggest that non-directional retinal ganglion cells can discriminate between
input sequences independent of the retina network.

Puthussery T, Venkataramani S, Gayet-Primo J, Smith RG, Taylor WR

In the primate visual system, the ganglion cells of the magnocellular pathway
underlie motion and flicker detection and are relatively transient, while the
more sustained ganglion cells of the parvocellular pathway have comparatively
lower temporal resolution, but encode higher spatial frequencies. Although it
is presumed that functional differences in bipolar cells contribute to the
tuning of the two pathways, the properties of the relevant bipolar cells have
not yet been examined in detail. Here, by making patch-clamp recordings in
acute slices of macaque retina, we show that the bipolar cells within the
magnocellular pathway, but not the parvocellular pathway, exhibit voltage-gated
sodium (NaV), T-type calcium (CaV), and hyperpolarization-activated, cyclic
nucleotide-gated (HCN) currents, and can generate action potentials. Using
immunohistochemistry in macaque and human retinae, we show that NaV1.1 is
concentrated in an axon initial segment (AIS)-like region of magnocellular
pathway bipolar cells, a specialization not seen in transient bipolar cells of
other vertebrates. In contrast, CaV3.1 channels were localized to the
somatodendritic compartment and proximal axon, but were excluded from the AIS,
while HCN1 channels were concentrated in the axon terminal boutons. Simulations
using a compartmental model reproduced physiological results and indicate that
magnocellular pathway bipolar cells initiate spikes in the AIS. Finally, we
demonstrate that NaV channels in bipolar cells augment excitatory input to
parasol ganglion cells of the magnocellular pathway. Overall, the results
demonstrate that selective expression of voltage-gated channels contributes to
the establishment of parallel processing in the major visual pathways of the
primate retina.

Smith RG, Delaney KR, Awatramani GB

The very first rays of the rising sun enrich our visual world with spectacular
detail. A recent study reveals how retinal circuits downstream of
photoreceptors 'functionally re-wire' to trade-off sensitivity for high spatial
acuity during night-day transitions.

Throughout the CNS, gap junction-mediated electrical signals synchronize neural activity on millisecond timescales via cooperative interactions with chemical synapses. However, gap junction-mediated synchrony has rarely been studied in the context of varying spatiotemporal patterns of electrical and chemical synaptic activity. Thus, the mechanism underlying fine-scale synchrony and its relationship to neural coding remain unclear. We examined spike synchrony in pairs of genetically identified, electrically coupled ganglion cells in mouse retina. We found that coincident electrical and chemical synaptic inputs, but not electrical inputs alone, elicited synchronized dendritic spikes in subregions of coupled dendritic trees. The resulting nonlinear integration produced fine-scale synchrony in the cells' spike output, specifically for light stimuli driving input to the regions of dendritic overlap. In addition, the strength of synchrony varied inversely with spike rate. Together, these features may allow synchronized activity to encode information about the spatial distribution of light that is ambiguous on the basis of spike rate alone.

Lipin, MY, Taylor WR, Smith RG. (2015)

J. Neurophysiology 2015 June DOI: 10.1152/jn.00413.2015

Summary

Direction selective ganglion cells (DSGCs) respond selectively to motion towards a "preferred" direction, but much less to motion towards the opposite "null" direction. Directional signals in the DSGC depend on GABAergic inhibition, and are observed over a wide range of speeds, which precludes motion detection based on a fixed temporal correlation. A voltage-clamp analysis, using narrow bar stimuli similar in width to the receptive field center, demonstrated that inhibition to DSGCs saturates rapidly above a threshold contrast. However, for wide bar stimuli that activate both the center and surround, inhibition depends more linearly on contrast. Excitation for both wide and narrow bars was also more linear. We propose that positive feedback, likely within the starburst amacrine cell or its network, produces steep saturation of inhibition at relatively low contrast, which renders GABA-release essentially contrast and speed invariant, and thereby enhances the signal-to-noise ratio for direction selective signals in the spike train over a wide range of stimulus conditions. This mechanism enhances directional signals at the expense of lower sensitivity to other stimulus features such as contrast and speed. This renders GABA-release essentially contrast and speed invariant, which enhances directional signals for small objects, and thereby increases the signal-to-noise ratio for direction selective signals in the spike train over a wide range of stimulus conditions. The steep saturation of inhibition confers to a neuron immunity to noise in its spike train because when inhibition is strong, no spikes are initiated.

Stincic T, Smith RG, Taylor WR. (2016)

Journal of Physiology 594:5685-5694 DOI: 10.1113/jp272384

Summary

Direction selectivity in the retina relies critically on directionally asymmetric GABA release from the dendritic tips of starburst amacrine cells (SBACs). GABA release from each radially directed dendrite is larger for motion outward from the soma toward the dendritic tips than for motion inwards toward the soma. The biophysical mechanisms generating these directional signals remain controversial. A model based on electron-microscopic reconstructions of the mouse retina proposed that an ordered arrangement of kinetically distinct bipolar cell inputs to ON and OFF type SBACs could produce directional GABA release. We tested this prediction by measuring the time-course of EPSCs in ON type SBACs in the mouse retina, activated by proximal and distal light stimulation. Contrary to the prediction, the kinetics of the excitatory inputs were independent of dendritic location. Computer simulations based on 3D reconstructions of SBAC dendrites demonstrated that the response kinetics of distal inputs were not significantly altered by dendritic filtering. These direct physiological measurements, do not support the hypothesis that directional signals in SBACs arise from the ordered arrangement of kinetically distinct bipolar cell inputs.

Percival KA, Venkataramani S, Smith RG, Taylor WR (2017)

J. Comp. Neurol. 2017 Mar 14. doi: 10.1002/cne.24207.

Summary

Directional responses in retinal ganglion cells are generated in large part by direction-selective release of GABA from starburst amacrine cells onto direction-selective ganglion cells (DSGCs). The excitatory inputs to DSGCs are also widely reported to be direction-selective, however, recent evidence suggests that glutamate release from bipolar cells is not directional, and directional excitation seen in patch-clamp analyses may be an artifact resulting from incomplete voltage control. Here we test this voltage-clamp-artifact hypothesis in recordings from 62 On-Off DSGCs in the rabbit retina. The strength of the directional excitatory signal varies considerably across the sample of cells, but is not correlated with the strength of directional inhibition, as required for a voltage-clamp artifact. These results implicate additional mechanisms in generating directional excitatory inputs to DSGCs.

Krizaj D, Smith RG (2017)

The rod photoreceptor is responsible for vision at night over the range of starlight through moonlight to twilight. Its structure is specialized to maximize photon capture, optimize metabolic efficiency and sustain continual synaptic activation. Rods are depolarized in the darkness, the light signal induced by capture of photons consists of a hyperpolarization that lowers the concentration of intracellular calcium ions within the rod terminal and suppresses release of the rod neurotransmitter glutamate. Mutations that change rod morphology, calcium signaling and/or glutamate release may compromise their viability and cause blindness.

Howlett MH, Smith RG, Kamermans M(2017)

PLoS Biol. 2017 Apr 12;15(4):e2001210.

Summary

An animal's ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, Ih, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent Ih. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by contrast, it is not a contrast adaptation mechanism in its strictest sense, as will be argued in the Discussion.